The broad objective is to understand the relationship between cellular metabolism and (a) membrane ionic permeabilities, (b) transmembrane ionic gradients and (c) subcellular compartmentation of various ions. Mitochondrial transport of Na plus ions via neutral exchange with protons will be stressed and the influence of this exchange upon mitochondrial pH gradients and distribution of anionic metabolites between mitochondrial and cytoplasmic compartments. The possible interplay between mitochondrial Ca plus 2 and Na plus transport will be studied to determine whether the translocation of Na plus may regulate the levels of Ca plus 2 within the cytosol. The experimental approach will involve comparative studies of isolated cells, mitochondria and submitochondrial particles to detail regulatory influences. Intact cell studies will involve alteration of intracellular ion levels together with specific alterations in the permeability of membranes with monovalent and divalent cation specific "ionophores". The influence of certain hormones upon plasma membrane permeability (e.g., glucagon, epinephrine, parathyroid hormone) and metabolism will form part of the above studies to examine the degree to which intracellular ions (especially calcium) determine the cellular response to these agents. The studies outlined will be applied to isolated liver cells in comparison to a selected variety of tumor cells to determine the extent to which the indicated ions and their translocation between compartments affects the oxidative and glycolytic metabolism of tumor cells as well as relevant hormonal influences.